The basic tenet of operant learning is tested in a laboratory by training rats to press a lever for a reward. When a rat learns to lever press for a sucrose reward, synaptic plasticity immediately occurs in the corticolimbic circuit. An example of this plasticity is the up regulation of an immediate early gene called Homerla. Recent work from Dr. Ann Kelley's laboratory has shown that Homerla has increased expression during the early learning, or acquisition, of operant learning in the dorsomedial striatum and the anterior cingulate cortex (Hernandez et al., 2006). What remains unknown is which cells in the dorsomedial striatum have upregulated Homerla expression, and what are the efferent and afferent projections of these cells. In addition, the anterior cingulate cortex sends a glutamatergic projection to the dorsomedial striatum. To date, the role of this corticostriatal projection and the postsynaptic glutamate receptors in operant learning has not been investigated. It is hypothesized that the .anterior cingulate cortical projection to the dorsomedial striatum mediates operant responding for a sucrose reward, and Homerla is upregulated in the corticostriatal cells that express enkephalin, a neuropeptide linked to food intake. To investigate these hypotheses, glutamate receptor antagonists will be microinjected into the dorsomedial striatum and anterior cingulate cortex to show the role of these areas in operant responding. In addition, tract tracing studies will be combined with in situ hybridization to determine the circuit connectivity of Homerla-expressing cells that are activated during operant responding for a sucrose reward. The knowledge gained from the aims of this proposal is important for furthering the understanding of the molecular changes that occur in different areas of the brain during initial learning. This initial learning that relates to procuring a reward is part of the early learning that initiates during addiction. Addiction is a disease that causes more than 550,000 deaths a year in the United States alone and has an estimated yearly economic cost of $432 billion. Understanding the neural substrates of addiction will help to produce treatments for this devastating disease.